Comparison of nociceptive behavior in prostaglandin E, F, D, prostacyclin and thromboxane receptor knockout mice.
Antagonist at specific prostaglandin receptors might provide analgesia with a more favourable toxicity profile compared with cyclooxygenase inhibitors. We analyzed nociceptive responses in prostaglandin D, E, F, prostacyclin and thromboxane receptor knockout mice and mice deficient of cyclooxygenase 1 or 2 to evaluate the contribution of individual prostaglandin receptors for heat, mechanical and formalin-evoked pain. None of the knockouts was uniformly protected from all of these pain stimuli but COX-1 and EP4 receptor knockouts presented with reduced heat pain and EP3 receptor and COX-2 knockout mice had reduced licking responses in the 2nd phase of the formalin assay. This was accompanied with reduced c-Fos immunoreactivity in the spinal cord dorsal horn in EP3 knockouts. Oppositely, heat pain sensitivity was increased in FP, EP1 and EP1+3 double mutant mice possibly due to a loss of FP or EP1 receptor mediated central control of thermal pain sensitivity. Deficiency of either EP2 or DP1 was associated with increased formalin-evoked flinching responses and c-Fos IR in dorsal horn neurons suggesting facilitated spinal cord pain reflex circuity. Thromboxane and prostacyclin receptor knockout mice showed normal pain behavior in all tests. The results suggest a differential, pain-stimulus and site-specific contribution of specific PG-receptors for the processing of the nociceptive stimuli, a differential modulation of nociceptive responses by COX-1 and COX-2 derived prostaglandins and compensatory and/or developmental adaptations in mice lacking specific PG receptors.
Popp
Laura
L
pharmazentrum frankfurt, ZAFES, Institut für Klinische Pharmakologie, Klinikum der Johann Wolfgang Goethe Universität Frankfurt, Theodor Stern Kai 7, Haus 74, Rm 437, 60590 Frankfurt am Main, Germany.
Häussler
Annett
A
Olliges
Anke
A
Nüsing
Rolf
R
Narumiya
Shuh
S
Geisslinger
Gerd
G
Tegeder
Irmgard
I
D000818:Animals; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000502:physiology; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D005557:Formaldehyde; D006358:Hot Temperature; D007091:Image Processing, Computer-Assisted; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000235:genetics / Q000523:psychology*; D010147:Pain Measurement / Q000187:drug effects; D010812:Physical Stimulation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000502:physiology; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology; D011982:Receptors, Prostaglandin / Q000235:genetics / Q000502:physiology*; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000502:physiology; D017482:Receptors, Thromboxane / Q000235:genetics / Q000502:physiology
D016760:Proto-Oncogene Proteins c-fos; D044006:Receptors, Epoprostenol; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D018078:Receptors, Prostaglandin E; D017482:Receptors, Thromboxane; C034671:prostaglandin F2alpha receptor; D005557:Formaldehyde; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C036293:prostaglandin D2 receptor